PROJECT SUMMARY The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer seeks to improve the understanding and treatment of breast cancer using an innovative and highly translational approach. The application consists of four projects, three cores, a developmental research program (DRP) and a career enhancement programs (CEP). Each project addresses a fundamental challenge that results in premature mortality or substantial morbidity. Project 1 brings together outstanding investigators to study mechanisms of resistance to CDK4/6 inhibitors. In estrogen receptor-positive breast cancer, we hypothesize that CDK2 hyperactivation is a cause of acquired resistance to CDK4/6 inhibitors. Elegant preclinical work will be complemented by a clinical study in which paired biopsies are obtained prior to initiation of CDK4/6 inhibitors and when resistance develops. In triple-negative breast cancer, we will evaluate the possibility that lysosomal sequestration of CDK4/6 inhibitors limits their therapeutic efficacy. In preclinical work, we will determine if this sequestration can be reversed administering chloroquine and will also conduct a trial of palbociclib/chloroquine in RB-intact triple-negative disease. Project 2 uses two ?co-clinical? trials ? running randomized human trials and mouse experiments largely in parallel ? to study two novel therapeutic approaches to enhance the anti- tumor immune response against HER2-positive breast cancers (CDK4/6 inhibition and dual PDL1 and 4-1BB targeting). Both approaches are based on our compelling preclinical data, and will include local and international collaborators. Project 3 tackles the challenge of breast cancer brain metastases. Leveraging our unique collection of xenografts derived from resected human brain metastases, and our experience conducting brain metastasis-specific trials, we will test the biologic and clinical impact of two novel systemic therapy regimens. Project 4 is focused on triple-negative breast cancer. We will perform comprehensive preclinical studies and clinical trials to determine whether targeted therapies can sensitize triple-negative tumors to immunotherapy. We will evaluate combinations of either PARP inhibitors or BET bromodomain inhibitors with immune checkpoint blockade. Core A, the Administrative Core, is the epicenter of scientific, fiscal and administrative oversight. It will lead efforts in planning and communication, and also houses the Patient Advocacy Committee. Core A will ensure that existing DF/HCC structures support the SPORE clinical research efforts. Core B, the Biostatistics and Computational Biology core, provides specialized expertise in biostatistics and management of genomic data. Core C, the Biospecimen and Pathology Core, will maintain tissue/blood repositories for the SPORE projects and for investigators outside of the SPORE. It also provides critical pathology services for the projects and will perform cutting edge assays. Core C also houses the Immuno-Oncology Sub Core. The DRP and CEP identify novel approaches to translational questions in breast cancer and support young investigators. Our SPORE in Breast Cancer is poised to make substantial contributions over the next five years and beyond.